Our project focuses on small cell lung cancer (SCLC), a common malignancy associated with poor prognosis. SCLC harbors RB1 and TP53 mutations in >90% of cases. Animal models based of deletion of these tumor suppressor genes in the mouse airway epithelium accurately recapitulate the histopathological progression and metastasizing capacity of human SCLC. Our research strategy aims to identify the mechanisms that p53 and Rb employ to suppress tumor formation and progression. Toward that goal, we have genetically engineered mice that allow not only inactivation of Rb and p53 to allow tumor formation and progression, but also the accurate genetic restoration of endogenous Rb or p53 once cancers have formed. Our hypothesis is that restoration of Rb and p53 function in SCLC will unleash latent tumor destructive programs that can be readily identified and then exploited to guide the development of therapeutic strategies that could recapitulate these effects. In this project, we propose to identify mechanisms of p53 and Rb action with a multi-pronged approach involving in vivo imaging, histological analyses, and molecular profiling.